Huntington's disease (HD) is a hereditary neurological disorder characterized by chorea, cognitive deficits and psychiatric symptoms. In HD there is a massive loss of striatal medium-sized spiny neurons (MSNs). MSNs can be divided into neurons of the direct and indirect striatal output pathways, based on the output nuclei they project to. MSNs of each pathway can also be separated based on molecular markers such as the expression of dopamine D1 receptors (D1) on direct and adenosine receptors (A2A) on the indirect pathway MSNs. MSNs of the indirect output pathway, which project primarily to the external segment of the globus pallidus (GPe), are believed to be affected earlier in the progression of HD compared to direct pathway MSNs. Most research in HD focuses on the striatum, but little has been done on examining the alterations that occur in striatal output nuclei of the direct pathway (substantia nigra pars reticulata (SNr)) or the indiret pathway, the GPe. I propose to examine how the direct and indirect pathway striatal output nuclei are altered in HD by studying changes that occur in mouse models of HD. I will use optogenetic techniques to regulate the firing of direct or indirect pathway MSNs to determine potential input alterations. Finally I will remove the mutant huntingtin gene from either the direc or indirect pathway MSNs. Then I will use optogenetics to stimulate the pathways and examine what alterations occur in an animal that has normal D1 or A2A MSNs while all other cells contain the mutant huntingtin protein.